Simufilam 50 mg or 100 mg for Mild-to-Moderate Alzheimer's Disease (REFOCUS-ALZ)
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The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. |
| ClinicalTrials.gov Identifier: NCT05026177 |
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Recruitment Status :
Active, not recruiting
First Posted : August 30, 2021
Last Update Posted : January 26, 2024
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| Condition or disease | Intervention/treatment | Phase |
|---|---|---|
| Alzheimer Disease | Drug: Simufilam Drug: Placebo | Phase 3 |
The primary objective of this study is to investigate the safety and efficacy of simufilam (PTI-125) in enhancing cognition and slowing cognitive and functional decline following 76-week, repeat-dose oral administration in participants with mild-to-moderate AD. Secondary objectives are to assess neuropsychiatric symptoms and to replicate the cerebrospinal fluid (CSF) biomarker effects observed in the two Phase 2 studies (PTI-125-03 and PTI-125-02) after 76 weeks of simufilam treatment. A third objective is to investigate the effect of simufilam treatment on plasma biomarkers as well as anatomical correlates of disease progression (brain volume [hippocampus, ventricles and whole brain]; and amyloid and tau deposition in the brain). A limited number of research sites will be invited to participate in sub-studies to assess the impact of simufilam on anatomical and biomarker endpoints, including: change from Baseline in CSF biomarkers (30 subjects/group); brain volume via magnetic resonance imaging (MRI) (50 subjects/group); and amyloid and tau positron emission tomography (PET) (40 and 50 subjects/group, respectively). Participants in both PET sub-studies will be required to have an MRI during the Screening Period and provide plasma for a biomarker sub-study. Participants in the tau PET sub-study will also provide additional plasma for a pharmacokinetic (PK) exposure response analysis. Changes from baseline for these imaging and fluid biomarkers represent additional secondary endpoints. The 90 subjects (30 per group) in the CSF sub-study will undergo lumbar puncture during the Screening Period and again at the Week 76 End-of-Treatment Visit to collect CSF biomarkers.
Safety will be evaluated by adverse event monitoring, vital signs, clinical labs, and the Columbia Suicide Severity Rating Scale at every visit. Subjects will undergo MRI during screening to ensure entry criteria are met (unless recent MRI confirms entry criteria); however, 150 subjects (50 subjects per treatment group) will also undergo repeat MRI assessments at Weeks 40 and 76 to assess both long-term safety and drug impact on brain volume as noted above. Resting electrocardiograms will be conducted at Baseline (Study Day 1) and Weeks 4, 40 and 76. A complete physical and neurological examination will be performed at screening, and brief examinations will be performed at all other visits. Weight will be measured during the Screening Period, at Baseline (Study Day 1) and at all other visits.
An independent Data Safety Monitoring Board (DSMB) will meet periodically to review subject safety assessments and determine if dosing may continue. A charter will be developed with specific guidance for the DSMB.
| Study Type : | Interventional (Clinical Trial) |
| Estimated Enrollment : | 1083 participants |
| Allocation: | Randomized |
| Intervention Model: | Parallel Assignment |
| Masking: | Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor) |
| Masking Description: | Randomized treatments will be assigned by subject numbers in a randomly generated numeric sequence. Randomization (1:1:1) will be stratified by low or high Mini-Mental State Exam (MMSE; 16-20 and 21-27). The randomization code will not be revealed to study subjects, Investigators, clinical staff, study monitors or the Sponsor until all subjects have completed therapy and the database has been finalized and locked. |
| Primary Purpose: | Treatment |
| Official Title: | A Phase 3, Randomized, Double-blind, Placebo-controlled, Parallel-group, 76-week Study Evaluating the Safety and Efficacy of Two Doses of Simufilam in Subjects With Mild-to-Moderate Alzheimer's Disease |
| Actual Study Start Date : | November 18, 2021 |
| Estimated Primary Completion Date : | May 2025 |
| Estimated Study Completion Date : | May 2025 |
| Arm | Intervention/treatment |
|---|---|
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Placebo Comparator: Placebo
Matching placebo, supplied by Cassava as coated tablets, and taken twice daily (b.i.d.) for 76 weeks
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Drug: Placebo
Matching placebo given b.i.d. for 76 weeks |
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Experimental: Simufilam 50 mg
Simufilam 50 mg, supplied by Cassava as coated tablets, and taken b.i.d. for 76 weeks
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Drug: Simufilam
Simufilam is a novel drug candidate designed to treat and slow the progression of AD. Simufilam binds with femtomolar affinity to an altered conformation of filamin A that is present in the brain of patients with AD and critical to the toxicity of Aβ42. In this study, simufilam will be given b.i.d. for 76 weeks at a dose of 50 mg or 100 mg.
Other Name: PTI-125 |
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Experimental: Simufilam 100 mg
Simufilam 100 mg, supplied by Cassava as coated tablets, and taken b.i.d. for 76 weeks
|
Drug: Simufilam
Simufilam is a novel drug candidate designed to treat and slow the progression of AD. Simufilam binds with femtomolar affinity to an altered conformation of filamin A that is present in the brain of patients with AD and critical to the toxicity of Aβ42. In this study, simufilam will be given b.i.d. for 76 weeks at a dose of 50 mg or 100 mg.
Other Name: PTI-125 |
- Change from baseline in the 12-item Alzheimer's Disease Assessment Scale - Cognitive Subscale (ADAS-Cog12) [ Time Frame: Baseline (Study Day 1) to Week 76 ]The change from baseline to Week 76 in the ADAS-Cog12, a psychometrician-administered battery comprised of several cognitive domains including memory, comprehension, praxis, orientation, and spontaneous speech. Scores range from 0 (best) to 80 (worst).
- Change from baseline in the Alzheimer's Disease Cooperative Study - Activities of Daily Living (ADCS-ADL) [ Time Frame: Baseline (Study Day 1) to Week 76 ]The change from baseline to Week 76 in the ADCS-ADL, a 23-item study partner questionnaire that covers both basic activities of daily living (ADL) and more complex ADL or instrumental ADL. Scores range from 0 to 78, with a lower score indicating greater severity of functional loss.
- Change from baseline in the integrated Alzheimer's Disease Rating Scale (iADRS) [ Time Frame: Baseline (Study Day 1) to Week 76 ]The change from baseline to Week 76 in the iADRS, where scores range from 0 to 146 with lower scores indicating worse performance.
- Change from baseline in the Neuropsychiatric Inventory (NPI) [ Time Frame: Baseline (Study Day 1) to Week 76 ]The change from baseline to Week 76 in the NPI, a 12-item study partner interview, which records the frequency and severity of common neuropsychiatric symptoms in dementia, as well as the level of study partner distress due to these neuropsychiatric problems. Scores range from 0 to 144, with higher scores indicating more frequent and severe symptoms, and greater levels of partner distress.
- Change from baseline in the MMSE [ Time Frame: Baseline (Study Day 1) to Week 76 ]The change from baseline to Week 76 in the MMSE, a set of standardized questions covering several target areas: orientation, registration, attention and calculation, short-term verbal recall, naming, repetition, 3-step command, reading, writing, and visuospatial cognitive assessment. Lower scores indicate more severe impairment.
- Change from baseline in the Clinical Dementia Rating Sum of Boxes (CDR-SB) [ Time Frame: Baseline (Study Day 1) to Week 76 ]The change from baseline to Week 76 in the CDR-SB, which characterizes 6 domains of cognitive and functional performance applicable to AD and related dementias: memory, orientation, judgment and problem solving, community affairs, home and hobbies, and personal care. Higher scores indicate more severe impairment.
- Change from baseline in the Zarit Burden Interview (ZBI) [ Time Frame: Baseline (Study Day 1) to Week 76 ]The change from baseline to Week 76 in the ZBI, a 22-item study partner questionnaire designed to assess the stress or burden experienced by caregivers of people with dementia, with a higher score indicating greater stress or burden.
- Changes from baseline in CSF neurogranin, neurofilament light chain, total tau, phospho-tau181 (P-tau181) and/or phospho-tau217 (P-tau217), soluble triggering receptor expressed on myeloid cells 2 (sTREM2), and Aβ42 [ Time Frame: Baseline (Study Day 1) to Week 76 ]Changes from baseline in CSF biomarkers of AD pathology, neurodegeneration, and neuroinflammation.
- Changes from baseline in brain volume via MRI [ Time Frame: Baseline (Study Day 1) to Week 76 ]Changes from baseline in hippocampus, ventricles, and whole brain volume.
- Changes from baseline in amyloid and tau PET [ Time Frame: Baseline (Study Day 1) to Week 76 ]Changes from baseline in amyloid and tau deposition in the brain
- Changes from baseline in plasma biomarkers P-tau181, P-tau217, and neurofilament light chain [ Time Frame: Baseline (Study Day 1) to Week 76 ]Change from baseline in plasma biomarkers of AD pathology and neurodegeneration
- Change from baseline in plasma biomarker SavaDx [ Time Frame: Baseline (Study Day 1) to Week 76 ]SavaDx is a novel plasma biomarker
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.
| Ages Eligible for Study: | 50 Years to 87 Years (Adult, Older Adult) |
| Sexes Eligible for Study: | All |
| Accepts Healthy Volunteers: | No |
Key Inclusion Criteria:
- Meets National Institute on Aging and Alzheimer's Association Research Framework criteria for individuals in clinical Stage 4 or 5 of the Alzheimer's continuum.
- Evidence for AD pathophysiology, confirmed prior to or during screening.
- MMSE score ≥ 16 and ≤ 27 at screening.
- Clinical Dementia Rating - Global Score must be 0.5, 1 or 2.
- If receiving background AD medications, the dosing regimen must be stable for at least 12 weeks prior to randomization. Chronic medications for conditions other than AD (such as depression) must be prescribed at a stable dose for at least 4 weeks prior to screening.
- The subject has not been a cigarette smoker or chewed tobacco for at least 3 years.
- Availability of a study partner.
- Individuals who have participated in a clinical study with an investigational drug targeting the underlying AD process may be permitted to participate in this study.
- Completed a COVID-19 vaccine primary series ("fully vaccinated") at least 2 weeks prior to randomization or had an unambiguous COVID-19 infection diagnosed more than 3 months before the start of the Screening Period.
Key Exclusion Criteria:
- A neurologic condition other than AD that significantly contributes to the subject's dementia.
- Any current primary psychiatric diagnosis other than AD if it is likely to confound cognitive assessment or ability to comply with study procedures.
- Geriatric Depression Scale (15-item) score > 8 (Note - a subject with a score > 8 may continue in screening if, in the judgment of the Investigator, the elevated score is not attributed to a major depressive episode).
- Suicidal ideation during the past 3 months or suicidal behavior during the past 12 months.
- Alcohol or substance use disorder within 2 years of screening.
- MRI presence of cerebral vascular or other significant pathology.
- History of transient ischemic attack or stroke within 12 months of screening.
- Seizure within 12 months of screening.
- Severe head trauma or head trauma considered likely to be contributing to the subject's cognitive impairment.
- Sleep apnea that is considered likely to be contributing to the subject's cognitive impairment.
- Insufficiently controlled diabetes mellitus or hypertension.
- Body mass index < 18.5 or > 37.5.
- History or diagnosis of clinically significant cardiac disease.
- Currently or previously prescribed/administered aducanumab, lecanemab, or any anti-amyloid monoclonal antibody, more than 2 doses.
To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.
Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT05026177
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| Study Chair: | Jim Kupiec, MD | Cassava Sciences |
| Responsible Party: | Cassava Sciences, Inc. |
| ClinicalTrials.gov Identifier: | NCT05026177 |
| Other Study ID Numbers: |
PTI-125-06 |
| First Posted: | August 30, 2021 Key Record Dates |
| Last Update Posted: | January 26, 2024 |
| Last Verified: | January 2024 |
| Individual Participant Data (IPD) Sharing Statement: | |
| Plan to Share IPD: | No |
| Studies a U.S. FDA-regulated Drug Product: | Yes |
| Studies a U.S. FDA-regulated Device Product: | No |
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Alzheimer Disease Dementia Brain Diseases Central Nervous System Diseases Nervous System Diseases |
Tauopathies Neurodegenerative Diseases Neurocognitive Disorders Mental Disorders |